Amyotrophic lateral sclerosis (ALS) is a devastating paralyzing disorder, killing patients within three to five years after onset.1-4 Clinical symptoms primarily result from progressive degeneration of motoneurons in the spinal cord and brain stem, largely sparing cognitive performance. The disease affects healthy individuals in the midst of their life, sporadically in >90% of cases without any family history. Although more males than females are affected before the age of 60 years, both genders are similarly affected at an older age.5 With the ageing population, increasingly more individuals suffer ALS—the third most common neurodegenerative disorder.6 
Many ALS patients first notice muscle weakness in their limbs (“limb-onset” ALS). In ˜25% of ALS patients, motoneurons first degenerate in the motor nuclei of the brain stem (“bulbar-onset” ALS), causing dysarthria, dysphagia and respiratory problems. Bulbar-onset ALS patients generally exhibit a faster and more aggressive disease progression than do limb-onset patients, but the latter eventually develop bulbar symptoms as well.
The precise cause of motoneuron degeneration in most cases remains largely enigmatic.2, 4, 7 SOD-1 mutations cause motoneuron degeneration in humans and, when overexpressed, also in transgenic mice. In fact, SOD-1G93A mice have become the gold standard animal model to assess the therapeutic potential of novel drug candidates.8 SOD-1G93A rats develop an aggressive form of ALS, but have not been used yet for evaluation of novel treatments.9, 10 No approved, effective cure is available yet for ALS. Riluzole is the only approved drug in some but not all countries, but it has a marginal benefit on survival, is costly, not free of side-effects and, importantly, ineffective on bulbar symptoms.16 
As ALS results from degeneration of motoneurons, neurotrophic growth factors, such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), insulin-like growth factor (IGF)-1, leukemia-inhibitory factor (LIF), cardiotrophin (CT)-1 and hepatocyte growth factor (HGF) have long been considered as therapeutic candidates for ALS. Gene transfer of GDNF but especially of IGF-1, using a retrogradelly axon-transported viral vector, has been shown to prolong survival of SOD-1G93A mice.17, 18 
Though clinical trials are underway,a the clinical applicability of gene therapy for ALS remains to be established and concerns about its irreversible nature, risk for adverse chromosomal effects, poor control of transgene expression, and large production needs still remain to be overcome. Delivery of recombinant neurotrophic growth factors, instead, is, therefore, an attractive therapeutic strategy, as it offers flexible control of the dose and duration of the administered protein. However, intrathecal infusion of BDNF,19 intracerebroventricular delivery of GDNFb or systemic administration of BDNFc or CNTF20 has, to date, not resulted in substantial clinical improvement in ALS patients, except for a 26% slowing of disease progression after IGF-1 delivery in one, but not in another, study.21, 22 At least part of the failure can be ascribed to the short half-life, immunogenicity, dose-dependent dual effect on neuronal survival versus apoptosis, undesired toxicity and limited ability to cross the blood-brain barrier after systemic delivery of these proteins.23-25 Another possible reason may relate to the fact that several of these factors, even while promoting survival of acutely injured motoneurons when exogenously supplied, may not play such a critical role in the endogenous control of adult motoneuron survival in a chronic disease such as ALS. a world-wide web at hdlighthouse.org/research/genetherapy/updates/0052als.phtmlb world-wide web at mdausa.org/research/ct-alsglia.htmlc world-wide web at alsa.org/news/news012801.cfm
We recently discovered that low VEGF levels are redundant for motoneuron development but cause adult-onset ALS-like motoneuron degeneration in genetically modified mice (WO0176620) and increase the risk of sporadic and familial ALS in humans as well.13-15 VEGF is a prototype angiogenic factor, implicated in vessel growth in health and disease.11, 12 To avoid immune problems and systemic side effects, to overcome the limited ability of VEGF to cross the blood-brain barrier, and to achieve maximal VEGF protein levels in the spinal cord parenchyma, we developed a strategy never previously used to examine the therapeutic potential of a recombinant protein in preclinical ALS studies, i.e., to deliver, intracerebroventricularly, recombinant VEGF for prolonged periods using a transgenic SOD-1G93A rat model of ALS. Surprisingly, we have found that extremely low levels of VEGF not only significantly ameliorates motoric performance, but also prolongs the survival time in a rat pre-clinical ALS model for an unexpected long time. The results show that low levels of VEGF can slow down the disease progression of patients suffering from ALS when administrated intracerebroventricularly.